Retroviral proteases have been shown previously to be only active as homodimers. They are essential to form the separate and active proteins from the viral precursors. Spumaretroviruses produce separate precursors for Gag and Pol, rather than a Gag and a Gag–Pol precursor. Nevertheless, processing of Pol into a PR (protease)–RT (reverse transcriptase) and integrase is essential in order to obtain infectious viral particles. We showed recently that the PR–RT from a simian foamy virus, as well as the separate PRshort (protease) domain, exhibit proteolytic activities, although only monomeric forms could be detected. In the present study, we demonstrate that PRshort and PR–RT can be inhibited by the putative dimerization inhibitor cholic acid. Various other inhibitors, including darunavir and tipranavir, known to prevent HIV-1 PR dimerization in cells, had no effect on foamy virus protease in vitro. 1H-15N HSQC (heteronuclear single quantum coherence) NMR analysis of PRshort indicates that cholic acid binds in the proposed PRshort dimerization interface and appears to impair formation of the correct dimer. NMR analysis by paramagnetic relaxation enhancement resulted in elevated transverse relaxation rates of those amino acids predicted to participate in dimer formation. Our results suggest transient PRshort homodimers are formed under native conditions but are only present as a minor transient species, which is not detectable by traditional methods.
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Research Article|
March 29 2010
Formation of transient dimers by a retroviral protease
Maximilian J. Hartl;
Maximilian J. Hartl
*Universität Bayreuth, Lehrstuhl für Struktur und Chemie der Biopolymere and Research Centre for Biomacromolecules, Bayreuth 95440, Germany
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Kristian Schweimer;
Kristian Schweimer
*Universität Bayreuth, Lehrstuhl für Struktur und Chemie der Biopolymere and Research Centre for Biomacromolecules, Bayreuth 95440, Germany
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Martin H. Reger;
Martin H. Reger
*Universität Bayreuth, Lehrstuhl für Struktur und Chemie der Biopolymere and Research Centre for Biomacromolecules, Bayreuth 95440, Germany
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Stephan Schwarzinger;
Stephan Schwarzinger
*Universität Bayreuth, Lehrstuhl für Struktur und Chemie der Biopolymere and Research Centre for Biomacromolecules, Bayreuth 95440, Germany
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Jochen Bodem;
Jochen Bodem
†Universität Würzburg, Institut für Virologie und Immunbiologie, Würzburg 97978, Germany
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Paul Rösch;
Paul Rösch
*Universität Bayreuth, Lehrstuhl für Struktur und Chemie der Biopolymere and Research Centre for Biomacromolecules, Bayreuth 95440, Germany
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Birgitta M. Wöhrl
Birgitta M. Wöhrl
1
*Universität Bayreuth, Lehrstuhl für Struktur und Chemie der Biopolymere and Research Centre for Biomacromolecules, Bayreuth 95440, Germany
1To whom correspondence should be addressed (email birgitta.woehrl@uni-bayreuth.de).
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Publisher: Portland Press Ltd
Received:
September 16 2009
Revision Received:
January 21 2010
Accepted:
February 08 2010
Accepted Manuscript online:
February 08 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 427 (2): 197–203.
Article history
Received:
September 16 2009
Revision Received:
January 21 2010
Accepted:
February 08 2010
Accepted Manuscript online:
February 08 2010
Citation
Maximilian J. Hartl, Kristian Schweimer, Martin H. Reger, Stephan Schwarzinger, Jochen Bodem, Paul Rösch, Birgitta M. Wöhrl; Formation of transient dimers by a retroviral protease. Biochem J 15 April 2010; 427 (2): 197–203. doi: https://doi.org/10.1042/BJ20091451
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